S149: LONG TERM OUTCOMES OF IFCG REGIMEN FOR FIRSTLINE TREATMENT OF PATIENTS WITH CLL WITH MUTATED IGHV AND WITHOUT DEL(17P)/TP53 MUTATION
Authors: N. Jain, P. Thompson, J. Burger, A. Ferrajoli, K. Takahashi, Z. Estrov, G. Borthakur, P. Bose, T. Kadia, N. Pemmaraju, K. Sasaki, M. Konopleva, E. Jabbour, N. Garg, X. Wang, R. Kanagal-Shamanna, K. Patel, W. Wang, S. Wang, J. Jorgensen, W. Lopez, A. Ayala, W. Plunkett, V. Gandhi, H. Kantarjian, S. O’Brien, M. Keating, W. Wierda
Journal: HemaSphere (2022)

Background: Chemoimmunotherapy with FCR has been an effective treatment for patients (pts) with CLL. Pts with mutated IGHV (IGHV-M) have favorable long-term outcomes after receiving FCR. We designed an investigator-initiated, phase 2 trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). We report here long-term outcomes with a median follow-up of 56.8 months. Aims: Investigate the role of combined chemoimmunotherapy and targeted therapy in CLL. Methods: Eligibility included age ≥18, IGHV-M, no del(17p)/TP53 mutation. Pts received 3 courses of iFCG. Pts achieving CR/CRi with undetectable MRD (U-MRD) in bone marrow (4-color flow-cytometry, sensitivity 10-4) after 3 courses of iFCG received ibrutinib with obinutuzumab (iG) for 3 cycles, followed by ibrutinib monotherapy for 6 months. All other pts received iG for 9 cycles (C4-12). Pts with marrow U-MRD at end of Cycle 12 stop all therapy. Response assessment was per 2008 iwCLL criteria with BM and CT scans every 3 months during the first year. After completion of all therapy, pts were followed by exam, blood counts and peripheral blood MRD every 6 months. NGS MRD (sensitivity 10-6) was performed in bone marrow in pts with available samples. Results: 45 pts initiated treatment. Median age was 60 [range, 25-71]. 69% had del(13q). After three cycles of iFCG, 39/45 (87%) pts achieved marrow U-MRD. Responses improved with continued therapy with 40/45 (89%) and 41/45 (91%) achieving marrow U-MRD after Cycles 6 and 12, respectively. Overall, 44/45 (98%) pts achieved marrow U-MRD as best response at any time during the study. The 5-year PFS and OS are 97.7% (95% CI 94–100%) and 97.8% (95% CI 94–100%), respectively. No pt had CLL progression or Richter transformation. One pt developed therapy-related MDS; this pt is being monitored for 38+ months without any therapy for MDS with normal blood counts. The sole event noted on both the PFS and OS curve is a pt death from heart failure. 41/45 pts completed 12 cycles of treatment (4 pts came off study prior to C12). All 41 pts achieved marrow U-MRD4 by flow-cytometry and per protocol, all 41 pts discontinued ibrutinib. After a median follow-up of 44.2 mos post-discontinuing ibrutinib, 6 pts had an MRD recurrence (defined as 2 consecutive values of ≥0.01% in peripheral blood by flow cytometry) at a median of 27.2 mos (range, 20.7-49.0 mos) after stopping all therapy. All 6 pts are being monitored with no clinical progression or active therapy; notably, all 6 pts were MRD+ at 10-6 by marrow NGS after the completion of 3 cycles of iFCG and 4/5 (1 missed sample) were MRD+ at 10-6 by marrow NGS after the completion of Cycle 12. Of the 16 pts who were marrow NGS MRD+ at 10-6 after 3 cycles of iFCG, 6/16 had an MRD recurrence in blood in follow-up vs. 0/20 who were NGS MRD negative/indeterminate (p = 0.004). Of the 12 pts who were marrow NGS MRD+ at 10-6 after Cycle 12, 4/12 had an MRD recurrence in blood in follow-up vs. 1/26 who were NGS MRD negative/indeterminate (p = 0.02). Image:Summary/Conclusion: The iFCG regimen, using only 3 cycles of chemotherapy (as opposed to 6 cycles of chemoimmunotherapy) achieves a very high rate of U-MRD in previously-untreated pts with CLL with IGHV-M CLL. No pt had disease progression with a median follow-up of close to 5 years. The 5-year PFS is 97.7%; this is favorable compared to 5-year PFS of ≈65% with FCR (CLL10), ≈70% with ibrutinib (A041202 trial), and 81% with ibrutinib (RESONATE-2) for IGHV-M CLL. Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity by NGS during therapy.